Widespread prostate specific antigen (PSA) screening underscores the need to identify causes and potential biomarkers of clinically more aggressive prostate cancer. Laboratory and clinical studies suggest that growth factors play an important role in prostate cancer proliferation, apoptosis and angiogenesis. These growth factors include insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF). In the Physicians Health Study (PHS), we recently showed that prediagnostic levels of circulating IGF-I were significantly associated with prostate cancer risk, while high levels of IGF binding protein, IGFBP-3, were associated with lower risk. Furthermore, our pilot study data suggests that plasma VEGF levels are significantly higher among patients with metastatic disease compared to patients with localized prostate cancer, and that plasma VEGF levels in advanced prostate cancer patients are prognostic for survival. To understand the underlying nature of these associations, we now propose to extend our previous work on IGF-I and IGFBP-3 to examine the associations of free IGF-I, IGFBP-I, a newly identified polymorphism of IGFBP-3, and circulating levels of VEGF in relation to risk of total and aggressive prostate cancer. We plan to obtain prostate cancer tissue samples from 828 cases to establish biologic links between these epidemiologic findings and phenotypic features of prostate cancer. We will assess the associations of these growth factors with tissue markers for disease progression, including IGF-I downstream signaling (HIF-1 and PTEN), markers of cellular proliferation rate (Ki67), apoptosis (TUNEL), and angiogenesis (VEGF expression and microvascular density). We will also examine the relation of these plasma and tissue markers with prostate cancer relapse and mortality. In the PHS, we have already assembled an extensive prospective clinical and serological database on prostate cancer with almost two decades of follow-up and 1336 prostate cancers. With this proposed study, we will expand upon our epidemiological findings and examine the biology underlying these intriguing results.